Gastrointestinal Stromal Tumors Flashcards
What is the most common sarcoma of the gastrointestinal (GI) tract?
Gastrointestinal stromal tumor (GIST).
What type of cells are GISTs derived from?
Mesenchymal cells known as interstitial cells of Cajal.
Where do GISTs most commonly present in the GI tract?
The stomach, followed by the small bowel, rectum, and colon.
What mutation is most commonly associated with GISTs?
Gain of function mutation in the KIT proto-oncogene, found in about 75% of GISTs.
What percentage of KIT-wild type (WT) tumors have mutations in platelet-derived growth factor receptor (PDGFR) α?
Approximately 80% of KIT-WT tumors.
What other mutation has been reported in KIT-WT GISTs, and what is its prevalence?
BRAF mutations, found in 13% of KIT-WT tumors.
Which familial syndromes are associated with KIT-WT GISTs?
Neurofibromatosis type 1 (NF1) and mutations in succinate dehydrogenase (SDH)
What is the role of Imatinib mesylate (Gleevec) in the treatment of GIST?
It is a TKI that targets ABL, BCR-ABL, KIT, and PDGFR, used in both metastatic and adjuvant settings for GIST management.
What is the benefit of neoadjuvant Imatinib therapy in GIST?
It may improve resectability of locally advanced tumors and allow for organ-preserving surgery in anatomically challenging locations.
What factors are used to estimate the risk of recurrence in GIST patients?
Tumor size
mitotic index
organ site
specific mutations in KIT.
What is the typical age and gender distribution for GIST?
in adults, median presenting age of 60 years and a slight male predominance
Where are GISTs most commonly found within the GI tract?
The majority are found in the stomach (> 50%), followed by the small bowel (25%–35%).
Which sections of the small bowel are most commonly affected by GISTs?
Most small bowel GISTs are found in the ileum and jejunum, with only 5% in the duodenum
How are GISTs commonly discovered?
Often incidentally during endoscopy, imaging, or unrelated surgeries.
What symptoms may present with larger GISTs?
Pain, fullness, early satiety, nausea, vomiting, weight loss, or a noticeable mass
Why might approximately one-quarter of GIST patients present with GI bleeding?
Due to erosion and ulceration of the underlying mucosa.
What is a rare but serious prognostic factor related to bleeding in GIST?
Tumor rupture into the peritoneal cavity, which may lead to life-threatening hemorrhage
Where does GIST typically metastasize?
Metastasis usually involves the liver or peritoneal cavity.
How common is lymph node involvement in adult GIST
It is rare, occurring in less than 5% of patients.
What characterizes pediatric GIST compared to adult GIST?
Pediatric GIST often involves SDH deficiency, is indolent, has female predominance, multifocal disease, frequent lymph node metastasis, and is universally resistant to imatinib.
What are familial GISTs associated with?
Germline mutations in KIT or PDGFRα, typically presenting as multifocal and indolent tumors
What are Carney’s triad and Carney-Stratakis syndrome?
Carney’s triad includes GIST, paraganglioma, and pulmonary chondroma
Carney-Stratakis syndrome involves GIST and paraganglioma
both associated with SDH mutations
Which other tumors might patients with NF1 mutations develop along with GIST?
gliomas, malignant peripheral nerve sheath tumors, and neurofibromas
What is the imaging modality of choice for the initial evaluation of a GIST?
Cross-sectional imaging with a computed tomography (CT) scan of the abdomen and pelvis with IV and oral contrast
What are the typical CT scan features of a GIST?
An enhancing mass arising in the wall of the stomach or small intestine
How can GIST tumors be grossly categorized?
As exophytic, endophytic, or mixed/dumbbell-shaped.
Why might smaller GIST tumors not be visible on a CT scan?
They may be obscured depending on the level of bowel or stomach distention and whether oral contrast was administered.
What large mass might be misinterpreted as a primary liver tumor on a CT scan?
A large hypervascular mass arising from the lesser curvature of the stomach.
When is MRI particularly useful in evaluating GIST?
For further delineating anatomy in periampullary and rectal tumors.
Is PET/CT necessary for the initial assessment of GIST?
No, but
it may be considered for detecting occult metastatic disease and assessing tumor response to TKIs.
What role does PET/CT have for NF1 patients in GIST evaluation?
It may help distinguish neurofibromas from GIST tumors
What is the next step in evaluation if a CT scan shows features suggestive of GIST?
Endoscopic evaluation, including endoscopic ultrasound (EUS) and fine-needle aspirate (FNA).
Why should percutaneous biopsies be avoided for small bowel GISTs?
Due to the risk of peritoneal dissemination.
What is the gold standard for confirming a GIST diagnosis?
Tissue analysis to rule out other potential tumors and confirm the presence of GIST.
What cell type is typically seen on pathology for GIST, and which marker is used for confirmation?
Spindle cells that stain positive for CD117 (KIT) on immunohistochemistry
Why is tissue analysis important beyond confirming GIST?
To detect additional genetic mutations (e.g., PDGFRα, BRAF, SDH, NF1) and guide targeted therapy.
For which GIST tumor locations is tissue diagnosis particularly necessary?
Tumors at the gastroesophageal junction (GEJ), periampullary duodenum, or rectum that may require a potentially morbid operation.
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What are the three clinicopathologic parameters that independently predict recurrence risk after complete resection of primary GIST?
Tumor size, mitotic rate, and tumor site
What tumor characteristics are considered poor prognostic indicators in GIST?
Tumor size greater than 5 cm
mitotic rate over 5/50 high-powered field (HPF)
nongastric tumor site.
How can identifying specific mutations (e.g., KIT, PDGFR, SDH) in GIST be beneficial?
It provides information on responsiveness to targeted therapy and progression-free survival (PFS) after resection.
What is the most common KIT mutation, and where does it commonly occur in GIST?
Exon 11 mutation, occurring in 65% of all GISTs.
What is the significance of deletions in codons 557 and 558 of KIT exon 11?
Tumors with these deletions are more likely to metastasize or recur compared to other mutation types.
What did the ACOSOG Z9001 study reveal about KIT exon 11 deletions and adjuvant imatinib?
Patients with KIT exon 11 deletions showed significant improvement in RFS with 1 year of adjuvant imatinib.
Which KIT mutation is associated with nongastric GIST and has more aggressive biology?
KIT exon 9 mutation, found in about 10% of GISTs.
What is the recommended imatinib dose for patients with KIT exon 9 mutations in metastatic unresectable GIST?
A higher dose of 800 mg daily, as opposed to the standard 400 mg.
What percentage of GISTs have PDGFRα mutations, and where are they typically located?
About 10%, almost always in the stomach.
What is the significance of the PDGFRα exon 18 (D842V) mutation in GIST?
It confers resistance to imatinib but responds to avapritinib therapy.
Which FDA-approved drug is used as first-line therapy for GIST patients with the PDGFRα exon 18 (D842V) mutation?
Avapritinib.
According to the National Comprehensive Cancer Network (NCCN), when is resection indicated for GISTs
For all GISTs greater than 2 cm in size in patients who are suitable surgical candidates
How are GISTs smaller than 2 cm managed if they are asymptomatic and indolent?
They can be observed with surveillance imaging
When might surgical resection be considered for patients with locally advanced or low volume metastatic GIST?
In selected cases, potentially along with neoadjuvant therapy
What is the guideline for imatinib therapy in patients undergoing surgery?
Imatinib can be stopped right before surgery and restarted once the patient tolerates oral medications
What is the guideline for other tyrosine kinase inhibitors (TKIs) in the perioperative period for GIST surgery?
Other TKIs should be stopped at least 1 week before surgery and restarted based on clinical judgment and recovery.
What areas should be examined upon entry into the abdominal cavity during GIST surgery?
The peritoneum, omentum, and liver should be checked for metastatic disease
Which gastric tumors are immediately visible upon entry?
Exophytic anterior and greater curvature gastric tumors.
How are posterior gastric tumors accessed during GIST surgery?
By retracting the left lobe of the liver to the right and entering the lesser sac through the greater omentum or gastrocolic ligament.
What method helps localize small intramural or endophytic gastric tumors during surgery?
Intraoperative endoscopy using a gastroscope.
What maneuver is required for accessing duodenal tumors beyond the first portion?
Extensive Kocher maneuver and potentially mobilizing the ligament of Treitz
How are ileal and jejunal GISTs identified during surgery?
By carefully running the small bowel from the ligament of Treitz to the terminal ileum
Why must GIST tumors be handled carefully during surgery
They are friable and may rupture, leading to a high risk of peritoneal recurrence
What is a key consideration regarding blood vessels in GIST surgery?
GISTs often have large arterial and venous collaterals, so care is needed to prevent significant blood loss.
Do GISTs typically require wide resection margins or lymphadenectomy like gastric adenocarcinoma?
No, GIST resection does not require wide margins or lymphadenectomy because they do not usually spread via lymphatics.
What is the goal of GIST surgery in terms of resection margins?
To achieve an R0 resection with microscopically negative margins.
What did the American College of Surgeons Oncology Group Z900 and Z9001 trials reveal about R1 resection in GIST?
No difference in recurrence-free survival (RFS) between R1 resection and R0 resection, regardless of imatinib treatment
What circumferential margin is recommended to achieve an R0 resection in GIST surgery?
A gross circumferential margin of 1 cm
What surgical approach is suitable for exophytic gastric GISTs with a narrow stalk on the greater curvature or fundus?
Wedge partial gastrectomy using surgical staples without compromising the lumen
Which areas of the stomach require direct visualization to safely resect GISTs without luminal narrowing
The antrum, incisura, lesser curvature, and gastroesophageal junction (GEJ)
What technique is used for excising gastric GISTs with a small negative margin?
Excision under direct visualization with a small margin (usually 1 cm) using cautery
When should neoadjuvant imatinib be considered for a GIST located at the GEJ?
For tumor downsizing before resection
What surgical approach is typically preferred for GISTs on the posterior aspect of the GEJ?
Open surgery, although minimally invasive options are possible
During open surgery for a GEJ GIST, what is the purpose of placing a bougie in the esophagus?
To avoid narrowing the GEJ during reconstruction
Describe the minimally invasive approach to excise a posterior GEJ GIST.
An anterior gastrotomy is created for visualization, excising the tumor with a small margin, closing the posterior gastrotomy in the direction of the widest lumen, placing a bougie, and closing the anterior gastrotomy.
What precaution is necessary when resecting GISTs from the lesser curvature of the stomach?
Careful dissection to preserve vagal nerve integrity.
What procedure should be performed if the vagal trunks cannot be preserved during lesser curvature GIST resection?
Pyloroplasty or pyloromyotomy.
When might total gastrectomy or esophagogastrectomy be necessary for GIST treatment?
For sizable tumors involving a large area of the lesser curvature or the gastroesophageal junction (GEJ), respectively.
What might necessitate en bloc resection in GIST surgery?
Massive tumors adherent to nearby organs such as the spleen, distal pancreas, or colon
What is the preferred approach if organ-preserving resection is desired for a large GIST
Neoadjuvant imatinib to achieve tumor downsizing and devascularization preoperatively
What is the second most common site of GISTs after the stomach?
The small bowel.
How are jejunal and ileal GISTs typically resected?
With open or minimally invasive techniques, with small bowel anastomosis performed intracorporeally or extracorporeally
What makes management of duodenal GISTs complex?
Their proximity to the pancreas and bile duct.
When should neoadjuvant imatinib be considered for a duodenal GIST?
When a pancreatoduodenectomy might be necessary for complete resection
What technique facilitates ampulla localization in cases of duodenal GIST near the ampulla?
Cholecystectomy with cystic duct cannulation using a 4Fr Fogarty catheter
How are small GISTs of the duodenum managed if they do not involve the periampullary region?
They can be resected without requiring pancreatectomy.
What surgical procedure is often required for periampullary GISTs involving the medial duodenal wall?
Pancreatoduodenectomy, even after neoadjuvant imatinib
How can small GISTs of the lateral wall of the duodenum’s second portion be managed?
They can be excised, with the defect closed by suture duodenorrhaphy or a Roux-en-Y duodenojejunostomy.
How are tumors in the third or fourth portion of the duodenum managed?
With segmental duodenectomy followed by primary duodenojejunostomy.
How common are rectal GISTs compared to colonic GISTs?
Rectal GISTs are much more common than colonic GISTs
What is the role of neoadjuvant imatinib in the treatment of large rectal GISTs?
It aids in tumor downsizing and sphincter preservation
How are small GISTs of the lower rectum typically excised?
Transanally, potentially using transanal endoscopic mucosal surgery
What is the current NCCN guideline for gastric GISTs under 2 cm with no concerning risk factors?
Active surveillance is recommended.
Under what conditions is endoscopic management of GIST considered feasible and safe?
For upper GI tract GISTs < 5 cm, after excluding high-risk features like high mitotic rate, enlarged lymph nodes, irregular margins, internal heterogeneity, and cystic spaces on EUS
Name three endoscopic procedures used for managing small GISTs
Endoscopic band ligation (EBL)
endoscopic submucosal dissection (ESD)
endoscopic full thickness resection (EFTR).
What are two advanced techniques combining laparoscopic and endoscopic approaches for GIST removal?
Laparoscopic endoscopic cooperative surgery (LECS) and nonexposed endoscopic wall-inversion surgery (NEWS).
What types of GISTs based on gastric wall location are suitable for endoscopic enucleation?
Types 1 and 2.
Which endoscopic techniques are appropriate for types 1 and 2 GISTs?
Endoscopic band ligation (EBL), endoscopic submucosal dissection (ESD), endoscopic mucosal dissection (EMD), endoscopic submucosal tunnel dissection (ESTD), and submucosal tunneling endoscopic resection (STER).
For which GIST types are EFTR, LECS, NEWS, and CLEAN-NET recommended?
Types 3 and 4, which are not amenable to endoscopic enucleation
What is CLEAN-NET in the context of GIST management?
A combination of laparoscopic and endoscopic approaches to neoplasia with a nonexposed technique.
What characterizes a Type I GIST in the gastric wall?
It has a very narrow connection with the proper muscle layer and protrudes into the luminal side like a polyp
How does a Type II GIST differ from Type I regarding its connection to the muscle layer?
Type II has a wider connection with the proper muscle layer and protrudes into the luminal side at an obtuse angle.
Where is a Type III GIST located within the gastric wall?
It is situated in the middle of the gastric wall.
In which direction does a Type IV GIST primarily protrude?
It protrudes mainly into the serosal side of the gastric wall.
What are the four layers of the gastric wall involved in GIST classification?
1: Mucosa
2: Submucosa
3: Circular layer of proper muscle
4: Longitudinal layer of proper muscle
When should neoadjuvant imatinib treatment be considered for nonmetastatic GISTs?
For tumors that are locally advanced, require multivisceral resections, or are in anatomically challenging locations where downsizing may reduce surgical morbidity
Which therapy should be used for patients with the D842V mutation of exon 18 in the PDGFRα gene?
Avapritinib, due to imatinib resistance
When should a follow-up contrast-enhanced CT scan be obtained after starting neoadjuvant imatinib?
Within 6 to 8 weeks.
How often is surveillance imaging typically performed during neoadjuvant imatinib therapy?
Every 3 months.
After how many months of neoadjuvant imatinib is further tumor downsizing unlikely?
Beyond 6 months
How does neoadjuvant imatinib differ from cytotoxic chemotherapy regarding perioperative management?
It can be continued up until surgery without affecting wound healing or causing immunosuppression
When can imatinib therapy be resumed postoperatively?
When the patient is eating normally and has regained bowel function.
What is the guideline for stopping avapritinib or other TKIs before surgery?
They should be stopped at least 1 week prior and restarted based on clinical recovery.
How did the long-term follow-up of the Z9001 study impact understanding of imatinib’s effects?
It showed that while imatinib controls residual disease, it does not eradicate it, as RFS curves converged after 74 months of follow-up
Which mutation was primarily associated with improved RFS in the Z9001 study?
Exon 11 deletion in the KIT gene
What did the SSG XVIII study compare, and what were its findings?
It compared 1 year vs. 3 years of adjuvant imatinib, finding that 3 years improved 5-year RFS (66% vs. 48%) and slightly improved overall survival (92% vs. 82%)
What was the focus of the PERSIST-5 trial, and what were its results?
It examined 5 years of adjuvant imatinib in high-risk GIST patients, showing effectiveness in preventing recurrence for those with sensitive KIT mutations
Which patients were included in the PERSIST-5 study criteria for high recurrence risk?
GISTs of any site ≥ 2 cm with ≥ 5 mitoses/50 HPF or any nongastric GIST ≥ 5 cm.
What is the primary benefit of extended adjuvant imatinib treatment in high-risk GIST patients?
It significantly reduces the risk of recurrence, especially in patients with sensitive KIT mutations.
What is the typical median time to disease progression with imatinib alone in GIST patients
Approximately 24 months.
What commonly causes disease progression in GIST patients on imatinib?
The development of secondary mutations in KIT, often in exons 13, 14, or 17.
How is imatinib resistance detected during radiographic surveillance?
By the appearance of enhancing nodules within a previously nonviable, necrotic tumor.
How frequently should imaging be performed for patients with recurrent or metastatic GIST on TKI therapy?
Every 3 months
When can surgical resection be considered in GIST patients with tumor resistance?
In carefully selected patients with limited disease burden, especially those with partial response to TKI therapy.
Which patients benefit most from surgery after TKI therapy in GIST management?
Those with partially responsive tumors, as opposed to those with rapid or multifocal resistance patterns
What is the recommended approach for hepatic GIST metastases?
Resection or ablation aimed at clearing all detectable tumor sites, with preservation of liver parenchyma
What is the management strategy for peritoneal GIST metastases?
Surgical resection, potentially requiring removal of adjacent organs
What is the postoperative management for GIST patients after resection of hepatic or peritoneal metastases?
Indefinite adjuvant TKI therapy or until recurrence develops
What is the partial response of imatinib-resistant GIST tumors to second-line TKI therapy?
Second-line TKIs, like sunitinib, can improve progression-free survival (PFS) from 6 weeks to 27 weeks.
How does third-line TKI therapy with regorafenib compare to second-line treatment?
Regorafenib improves PFS from 0.9 to 4.8 months, showing diminishing returns with each line of therapy.
Adjuvant imatinib should be used for at least ?
3 years in patients at high risk for disease recurrence predicted by individualized nomograms.
Schematic approach to patients with gastrointestinal stromal tumor (GIST).
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primary tumors treated with adjuvant imatinib, tumor density should be assessed by CT at
4 weeks to document response to therapy.
If GIST nomogram predicts a high or intermediate risk of recurrence
adjuvant imatinib should be continued for at least 3 years, possibly chronically
Surveillance after resection of GIST should include
CT of abdomen and pelvis every 3 to 6 months for
3 to 5 years and then annually
